Parkinson’s disease (PD) Newsletter:

Our Neurogenetics group at the National Institutes of Health in Bethesda, MD
works on neurodegenerative disorders. Our Laboratory lead by Dr. John Hardy,
Laboratory Chief at the National Institute on Aging (NIA) is comprised of
several parts: Molecular Genetics (led by Dr. Andrew Singleton), Cell
Biology (led by Dr. Mark Cookson), and Bioinformatics (led by Dr. Jamie
Duckworth). Our group also includes a clinical team.  The clinical team is
spearheaded by investigators from the National Institute on Neurological
Disorders and Stroke (NINDS) (including Drs. Ravina and Gwinn-Hardy) and
includes others from the National Human Genome Institute (NHGRI, Dr.
Nussbaum) and the NIA (Dr. Salerno). We also have collaborators inside the
NIH and outside at other institutions.

Since 1986, our lab has had a very simple philosophy: find the genes and
gene mutations that cause or contribute to neurological disease. So how do
we do this? A successful approach that we’ve used in the past is to find
families in which a disease is more common than you would expect by chance.
Take the family below for example; in this family there are a set of
grandparents with four children. Two of these children also have children (2
girls with PD in one instance, 2 boys and 1 girl in the other). Let us say
the people shaded in red have PD the ones in yellow have no symptoms. The
incidence of PD in the general population is thought to be so the number of
PD cases observed in this family is well in excess of what you would
normally expect. When a situation like this occurs it generally means one of
two things; there is a shared environmental factor that is causing the
disease or there is a genetic predisposition to disease. The occurrence of
PD in multiple generations in this family makes the second option the more
likely.

The genome is comprised 22 pairs of chromosomes and 2 X chromosomes (female)
or an X and a Y chromosome (male). Every cell in the body contains a copy of
the genome. We inherit one of each pair of chromosomes from our father and
the other from our mother. In turn we then pass on a mixture of our fathers
and mothers chromosomes to our children. Within these chromosomes are around
35,000 genes which contain the instructions on how to produce proteins. Most
often diseases such as the inherited PD seen in this pedigree are caused by
a single change in a single gene. Currently it is impossible to look at all
35,000 genes at once, so, in order to find this change we have to narrow
down the number of genes we need to examine. To do this we use a technique
called linkage. Basically we examine small regions of the genome and follow
the inheritance of that section through a family. Lets look at the family
again, with additional genetic information.


Imagine the colored bars represent a small section of the genome (let’s say
about 1/1000th). Again it’s important to remember that each section of the
genome comes as a pair, half inherited from your father and half from your
mother. Using “markers” we can distinguish between the two halves of these
pairs and trace their inheritance through a family. This allows us to find a
section of the genome that is always inherited with disease. Geneticists
call this segregation and you can see that in this family the bright green
section of the genome is always inherited with disease. This tells us that
the gene defect is somewhere around this region of the genome. The larger
the family is the more confident we can be of this result. Usually this
stage will allow us to narrow down the number of genes we are interested in
to 300 or so. We then systematically examine each gene for a change (called
a mutation) that is likely to cause disease. Technological advances over the
last 10 years has meant that the whole process from finding families to
finding mutations is a lot quicker, however this approach still generally
takes 5 to 15 years of research!

So given the incredible amount of time and effort needed to find these
mutations why do we do it? These discoveries allow us and others to transfer
those genes and mutations into cells and mice in order to make a model which
helps the field to better understand disease processes. As more is
understood about the disease progression we can then use these models to
test therapies. It is only by appreciating how a disease begins and
progresses that scientists can make informed attempts at halting or
reversing disease progression. We have been a key laboratory in furthering
the basic understanding of Alzheimer’s disease progression and are now
applying these techniques to a host of other diseases, including PD, Stroke,
Dystonia, and Restless Legs Syndrome to name a few.

As part of our research, we collect families and individuals with movement
disorders, which includes PD. Our research focuses on family collection and
using genetics as a tool to find new genes. Because genes are most easily
discovered in large families, we are very interested in learning about
individuals with PD who have a family history of this disorder. Finding new
genes or expanding the knowledge of genes previously described for PD will
help to decipher the biological pathways involved in disease development. We
would like to follow up on previous research performed by our laboratory and
other research laboratories on PD. In order to do this, we need
participation from families with a history of PD and participation from
individuals with no family history of PD. For families with a history of PD,
it is important that both affected and unaffected family members participate.

If you are interested in participating in our research on PD or have study
related questions, please contact our clinical coordinator listed below by
email or telephone. For more information about our research group or our
location: http://www.grc.nia.nih.gov/branches/lng/lng.htm.


Amanda Singleton
NIH/NINDS
Bldg. 10/ 6C103A
9000 Rockville Pike
Bethesda, MD 20850
[log in to unmask]
301-402-6231
301-480-0335 fax

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